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Researchers from Osaka University have shown that mesenchymal stem cells suppress the onset of type 1 diabetes induced by anti-cancer drugs

Figure. Diabetes incidence by cancer immunotherapy could be reduced by mesenchymal stem cell therapy. Modified from Graphical Abstract of Diabetologia, CCO.

Immune checkpoint inhibitors are widely used to treat a variety of cancers; however, one serious side effect is the onset of type 1 diabetes. Now, researchers from Osaka University have discovered that stem cell therapy may protect against such side effects.

One strategy by which tumor cells evade recognition by the immune system is by upregulating factors that interfere with immune cell signaling – a process known as immune checkpoint inhibition. For example, the upregulation of programmed death-ligand 1 (PD-L1) leads to increased binding to its receptor (PD-1) on T cells of the immune system, inhibiting T cell activation. The therapeutic use of immune checkpoint inhibitors can reverse these effects, restoring immune system surveillance and tumor cell killing. However, these anti-cancer drugs are accompanied by autoimmune side effects, including the onset of type 1 diabetes.

Type 1 diabetes is a serious autoimmune disease that develops when the level of insulin produced by the islets of Langerhans in the pancreas drops below the required threshold, resulting in the body’s inability to control blood sugar levels. Such patients are dependent on insulin therapy. When insulin-producing cells are completely lost, the control of blood sugar levels becomes severely compromised, resulting in clinical complications, impaired quality of life, and a poor prognosis. Strategies for the prevention or cure of type 1 diabetes are currently lacking.

Mesenchymal stem cell (MSC) therapy is the most commonly used type of cell therapy. MSCs secrete factors that contribute to tissue regeneration, anti-fibrosis activity, and modulation of immune functions.

In the recent study at Osaka University, researchers showed that MSCs have therapeutic potential against immune-related adverse events. As Emi Kawada-Horitani, the lead author of the study, explains “We examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a mouse model. First, we induced diabetes in the mice by administering a purified PD-L1 monoclonal antibody. Then, we injected human adipose-derived MSCs and analyzed immune cells in the pancreatic secretions.” Kawada-Horitani continues, “Inhibition of the PD-1/PD-L1 interaction with an anti-PD-L1 antibody resulted in a diabetes incidence of 64% among the mice, compared with 19% when the mice were also administered MSCs.”

Inhibition of the PD-1/PD-L1 interaction causes various changes in the immune system—most notably, the massive accumulation of immune cells (particularly macrophages) in the islets of Langerhans in the pancreas, disrupting insulin production.

“We found that MSCs effectively prevented this influx of immune cells,” corresponding author Shunbun Kita explains, “thereby avoiding the detrimental effects on pancreatic cells.” They further showed that MSCs secrete factors (such as exosomes) that protect the pancreatic cells against immune attack.

Their findings suggest that MSC transplantation can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and is therefore worthy of consideration as a new type of adjuvant cell therapy.

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The article, “Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade,” was published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) at DOI: https://doi.org/10.1007/s00125-022-05708-3

Summary: Researchers from Osaka University report that the therapeutic use of mesenchymal stem cells is effective at suppressing the onset of diabetes induced by immune checkpoint inhibitors used to treat cancer. Mesenchymal stem cells therefore have potential as a new type of adjuvant cell therapy.

Tweet 1: Stem cell therapy prevents certain side effects of cancer drugs
Tweet 2: Stem cells prevent type 1 diabetes caused by certain types of cancer drugs

Primary Keyword: Medical treatment
Additional Keywords: Cancer treatment, stem cell therapy, stem cell transplantation, side effects, type 1 diabetes

Method of Research: Experimental study

Subject of Research: Animals

Conflicts of Interest Statement: Osaka University have filed a patent claim regarding adiponectin-mediated stimulation of exosome production: Japanese Patent Application JP2017-131172 (inventors: SK et al). Osaka University and ROHTO Pharmaceutical have filed patents regarding improved MSC therapy for heart failure (JP2019-234288 [inventors: SK et al]), and the new MSC therapy for diabetes (JP2021-26666 [inventors: SK et al]). H. Nishida and YH are employees of ROHTO Pharmaceutical. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

Title: “Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade”
Journal: Diabetologia
Authors: Emi Kawada-Horitani, Shunbun Kita, Tomonori Okita, Yuto Nakamura, Hiroyuki Nishida, Yoichi Honma, Shiro Fukuda, Yuri Tsugawa-Shimizu, Junji Kozawa, Takaaki Sakaue, Yusuke Kawachi, Yuya Fujishima, Hitoshi Nishizawa, Miyuki Azuma, Norikazu Maeda, and Iichiro Shimomura
DOI: 10.1007/s00125-022-05708-3

Funded by: Japan Agency for Medical Research and Development, Japan Science and Technology Agency